One of the key items of information that physicians need to know for the selection and timing of medical treatment is the state of diseased tissue and the likelihood it will return to normal viability in response to therapy. Many methods are used to assess tissue health including the history of the patient's symptoms, physical examination, and laboratory and imaging studies of tissue biochemistry and anatomy. Abnormal anatomy, signal changes reflecting the state of tissue water and basic physiologic measurements such as water diffusion and blood flow are among the methods used. These methods are useful but are themselves secondary signs of more fundamental properties of tissue metabolism and potential. Magnetic resonance imagery (MRI) is one of the most frequently used imaging methods to assess tissue viability and although it is a highly sensitive and specific tool, it also depends primarily on secondary signs of tissue health to assess tissue viability.
The ability of MRI procedures to distinguish between subareas within a given tissue area is often limited. One example of this concerns the determination of penumbra in a stroke patient. The importance of this determination is apparent from the fact that there are an estimated 731,000 strokes and 4 million stroke survivors annually in the United States alone, making stroke a major cause of long-term disability. Considering also the mortality and morbidity caused from cardiac arrest, traumatic brain injury and perinatal asphyxia, it is easily understood that the economic and social burden of CNS injury is huge. Beyond the direct hospitalization and treatment costs, the indirect costs of lost productive years is of importance because ischemic stroke is prevalent in the older population and traumatic brain injury and perinatal asphyxia are diseases mainly of the young and newborns, respectively. Thus, indirect costs are even higher than direct costs for traumatic brain injury and perinatal asphyxia.
In the assessment of acute cerebral ischemic stroke (and cerebral tissue at risk for ischemic injury in chronic vascular stenosis), a key item of information needed for therapy decisions is an accurate differential identification of normal tissue, tissue injured beyond recovery (the ischemic infarct “core”) and tissue at risk for permanent injury but potentially salvageable with therapy (the ischemic infarct “penumbra”). The infarct core is the zone of absent cerebral blood flow (CBF) or low CBF with tissue metabolism below a viable threshold (CMRO2), usually identified on MRI as a zone of severely restricted diffusion indicating the failure of cellular energy metabolism. The penumbra, tissue that remains viable but has reduced blood flow and is at high risk of energy failure and cell death, has two zones. The region of the penumbra called the “oligemic” zone is where prolonged reduced blood flow may be compatible with tissue survival and therapy may only be needed to prevent further flow reduction. Thus, the compensation for early or mild reduced blood flow in stroke (Stage 1) takes the form of vasodilation and increased coronary blood volume which maintains blood flow sufficiently to allow normal cellular metabolism to be maintained at a normal oxygen extraction fraction (OEF). With more severe blood flow reduction (Stage II), the vasodilation capacity is exceeded, normal flow cannot be maintained and OEF is increased because more oxygen must be extracted per volume of blood to maintain normal cellular metabolism. This is the true ischemic penumbra and is also called the zone of “misery perfusion”. This tissue will not survive without treatment to improve blood flow. The end point of this trend is extreme or prolonged blood flow reduction leading to failure of cellular energy metabolism, apoptosis, cell death and reduction of OEF below normal in response to the absence of oxygen demand. “Necrotic” cell death occurs because the mitochondria are incapable of maintaining ATP production with inadequate oxygen delivery. This “oxidative stress” also activates a mitochondrial trigger for “apopotic” cell death, or programmed cell death mediated by a cascade of protein activation and DNA injury. Similar principles apply to the assessment of tissue at risk in chronic vascular stenosis where elevated OEF identifies tissue at the highest risk of developing infarction.
When normal perfusion pressure is not maintained, reflex vasodilation occurs to maintain normal blood flow. This response, as well as the reflex vasoconstriction observed with increased perfusion pressure, is known as autoregulation or Stage 1 hemodynamic compromise. It maintains normal flow by reducing the vascular resistance to arterial inflow. With further reductions in perfusion pressure, the capacity of autoregulatory vasodilation to maintain normal blood flow is overcome and blood flow begins to decrease. Although the delivery of oxygen falls, the brain can increase the amount of oxygen it extracts from the blood (the oxygen extraction fraction or OEF) to maintain normal cerebral oxygen metabolism and function. This phenomenon of reduced blood flow and increased oxygen extraction is the reason for “misery perfusion” or Stage 2 hemodynamic failure. Once oxygen extraction becomes maximal, further decreases in perfusion pressure (and consequently blood flow) will lead to disruption in normal oxygen metabolism and ultimately to infarction.
At present, regional measurements of OEF can be made only with positron emission tomography (PET) using O-15 labeled radiotracers. Both absolute values and side-to-side ratios of quantitative and relative OEF have been used for the determination of abnormal from normal. MRI measurements using pulse sequences sensitive to deoxy-hemoglobin, which is increased in regions with increased oxygen extraction, are just beginning to be be developed to provide similar information.
The present invention is based on a recognition that tissue blood flow, molecular oxygen delivery, oxygen metabolic rate and oxygen extraction fraction can all be measured with a form of MRI which employs 17O2. While all of these parameters are important for the assessment of the metabolic state of tissue, the oxygen extraction fraction (OEF) is the variable which is the most sensitive and specific for tissue in a state of “oxidative stress” and so is the key predictor of tissue viability because total oxygen consumption may appear to be constant due to the tissue's ability to compensate for locally reduced oxygen delivery. Reductions of blood flow, oxygen delivery and oxygen metabolic rate below normal levels do not specifically indicate whether the oxygen supply is deficient to tissue with normal metabolic demand (ischemia or hypoxemia) or appropriate for tissue with a reduced metabolic demand (metabolically suppressed, stunned or hibernating or dead tissue). Elevation of the OEF specifically indicates that there is a tissue metabolic demand for oxygen that is not being adequately met by the oxygen supply for the blood. More precisely, there is an increased gradient along which oxygen is diffusing between the higher concentration in blood and the lower concentration in tissue, produced by the rate of oxygen consumption in tissue mitochondria. This increased concentration gradient induces a greater percentage of blood oxygen to be released from hemoglobin and transported to the tissue. OEF is not elevated, but is reduced in metabolically suppressed or dead tissue because the blood-tissue oxygen concentration gradient is minimized. The prediction of tissue viability by OEF is based on the frequent observation that substantial, prolonged OEF elevation directly precedes cell death in a variety of tissues. The oxidative stress indicated by elevated OEF leads to cell death by necrosis from mitochondrial energy depletion (failure of ATP production) and/or mitochondrial triggering of the molecular cascade leading to apoptosis, or “programmed cell death”.
The quantitative measure of oxygen removal from blood, the oxygen extraction fraction (OEF), is the percent of oxygen removed per unit volume of blood, caused by oxygen diffusion along the gradient from the high concentration in the blood to the low concentration in the metabolizing tissue. Normal brain tissue OEF is approximately 40% and may be as high as 60-70% in the subarea of penumbra misery perfusion. In acute ischemia, tissue with elevated OEF is likely to progress to cell death unless normal blood flow is restored (e.g. by thrombolysis) or metabolic demand is reduced (e.g. by hypothermia). In transient ischemic attack (TIA) or chronic vascular stenosis, tissue with elevated OEF is at risk for permanent injury if blood flow is reduced below the marginal level maintaining tissue viability.
It is important to initiate acute therapy promptly to prevent penumbra tissue from progressing to infarction and thereby preserve, at least to some degree, the normal functioning of this brain tissue. These acute therapies have no effect on the ischemic core or infarction but involves a high degree of risk. For example, anti-coagulant therapy can be dangerous to the patient in that normal coagulation is suppressed. Because of the possible adverse effects, the treating physician must evaluate the risks and benefits of the therapy, an evaluation which includes consideration of the likelihood of converting the penumbra tissue into “normal” tissue. This requires estimating how much true ischemic penumbra tissue exists.
In the absence of other factors, one of the principle items of information on which the treating physician makes an evaluation of the risk and benefits is the amount of time since the stroke apparently occurred. Since the progression from penumbra to infarction is relatively rapid, usually measured in terms of hours, and there is a lack of precession about when the cerebral schema event commenced, the treating physician is essentially forced to make a risk/benefit evaluation based on the limited information which may be available. A diagnostic procedure which will assist the physician in making an evaluation is clearly desirable. Positron emission tomography (PET) has been found to provide detailed insight into the changes which occur after a cerebral ischemia. PET detects viable but hyperperfused tissue that is characterized by an elevated OEF and accessible to acute therapy. It is thus capable of providing a relatively accurate identification of the true ischemic penumbra tissue. However, PET involves the use of a radioactive isotope of oxygen, 15O, and a substantial radiation dose. Consequently, the substitution of data from stroke magnetic resonance imagery induced markers has been recognized as desirable. But stroke MRI induced markers for tissue integrity or cerebral profusion do not satisfactorily identify the penumbra.
Currently, the most frequently used MRI methods for evaluating the health of brain tissue and the risk of infarction are bolus-contrast perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI). PWI is performed by injecting a rapid bolus of gadolinium-chelate contrast agent intravenously while monitoring its passage through the brain circulation with rapid MR imaging, at approximately 1 image per second. Spatial maps of cerebral blood volume (CBV), tissue circulation mean transit time (MTT) and cerebral blood flow (CBF) are calculated using the central volume principle. These maps are compared to the diffusion weighted images which show infarcted tissue as high signal, representing restricted diffusion in cells that have undergone complete failure of energy metabolism. When this comparison shows areas of reduced perfusion outside the restricted diffusion infarction, a PWI-DWI “mismatch” is present and is considered a surrogate marker of the metabolic penumbra.
The major limitation of the PWI-DWI mismatch assessment of tissue at risk is that it is based on indirect measures of the tissue metabolic status. The practical effect of this limitation was studied in order to evaluate the accuracy of using mismatch to indicate penumbra and the study found that mismatch overestimated the volume of penumbra, and therefore the tissue at risk which was subject to acute therapy. See Sobesky et. al., Does the Mismatch Match the Penumbra?, Stroke, 2005; 36:980-985. Accordingly, mismatch as determined by MRI procedures provides inaccurate information to the treating physician. But an MRI procedure has the advantages over PET of an absence of ionizing radiation exposure to the patient and medical personnel, and the absence of a need for an expensive, complex, on-site cyclotron and radiation chemistry lab. An MRI procedure which more accurately identifies penumbra information for the treating physician that mismatch is clearly desirable.
The present invention is based, in part, on the recognition that the mismatch zone includes a mix of tissue with reduced flow and normal OEF (“oligemic” perfusion) and tissue with elevated OEF (“misery” perfusion). In the oligemic perfusion zone, cellular oxygen demand is close to the oxygen level supplied by blood flow and the tissue is likely to remain viable with continued low perfusion. In the misery perfusion zone, cellular oxygen demand is well above the oxygen level supplied by blood and the tissue is likely to progress to infarction unless perfusion is improved or returned to normal. It is also based, in part, on the recognition that the PET analysis is not effected by the oxygen uptake compensation by the tissue in the same way that MRI mismatch analysis is effected. It also takes advantage of the stable nature of the 17O2 isotope compared to the 2 minute half-life decay of 15O2 which will allow distribution of an 17O2 viability agent in an “off the shelf” form to the large installed base of MRI scanners now in operation.
It is the object of this invention to provide a new method for differentiating or monitoring tissue response to stress, such as for instance, determining penumbra brain tissue in a stroke patient, using proton magnetic resonance imaging. This and other objects of the invention will become apparent from the following detailed description.